7. PROJECT SUMMARY/ABSTRACT Temporal lobe epilepsy (TLE) is the most common form of epilepsy, a debilitating disease that affects 50 million people in the world. In TLE, seizure onset is typically localized to an epileptogenic zone (EZ) in the mesial temporal lobe. Unfortunately, the negative effects of TLE are not limited to the EZ. Previous studies have shown widespread neocortical decreases in resting state functional connectivity (RSFC) in patients with TLE versus healthy controls and have related these RSFC decreases to neuropsychological impairments. Previous works have resulted in the ?network inhibition hypothesis,? that proposes that focal seizures may influence widespread neocortex by affecting deep arousal structures that are important for cortical activation. The hypothesis of this proposed work is that recurrent seizures in patients with TLE result in altered connectivity between arousal structures and the neocortex, leading to decreased neocortical connectivity and impaired neurocognition. To explore this hypothesis, this work will use an innovative, multimodal approach to overcome the limitations of prior TLE studies to elucidate brain network dysfunction and its clinical implications. First, this study will use functional magnetic resonance imaging (fMRI) to measure RSFC between arousal center structures and the neocortex in pre-operative patients with TLE. Then, to determine if surgical treatment results in improved connectivity in patients that achieve seizure freedom after surgery, fMRI connectivity analyses will be repeated at least one year after surgery (Aim 1). Second, to understand the clinical implications of arousal center network perturbations, pre- and post-operative RSFC patterns will be related to clinical measures of disease severity and specific neurocognitive parameters. This work expects that larger RSFC perturbations will be associated with increased disease severity and worse neurocognitive performance, and that after surgery patients with seizure freedom will experience improvement in neurocognitive domains most closely related to frontoparietal function (Aim 2). Third, thus far, no direct relationship has been shown between ictal network perturbations and interictal connectivity disturbances. This work will address this knowledge gap by performing dynamic functional connectivity (DFC) analyses using intracranial EEG during and between CPS and SPS. This work expects that during CPS, but not SPS, neocortical DFC will be decreased compared to interictal connectivity (Aim 3). This proposed fellowship will provide research training in in a collaborative research atmosphere with expert mentors in translational neuroscience and engineering research. Research training will be conducted in an environment that combines an academic medical center with a level 4 epilepsy center, world class imaging institute, and engineering all on one campus, ensuring an environment uniquely suited to excellent training in all aspects of this proposed work. Studying arousal network dysfunction in TLE may lead to improved neuromodulation targets or behavioral therapies for this disorder and may improve our mechanistic understanding of Sudden Unexplained Death in Epilepsy (SUDEP).